PROJECT SUMMARY Progressive apraxia of speech is a neurodegenerative speech motor planning disorder that affects the production of speech. In the 1st cycle of the R01 we demonstrated that progressive apraxia of speech is associated with progressive degeneration of both the grey and white matter of the brain, with degeneration spreading throughout the brain from a relatively focal starting point, and we showed that regional changes correlated to clinical decline. However, the neurobiological mechanisms underlying these structural changes and disease progression remain elusive and represent a gap in knowledge. Understanding disease mechanisms will be critical for the development of appropriate therapies and for assessing the efficacy of treatments. The primary goal of our 2nd cycle is, therefore, to utilize advanced neuroimaging techniques to assess the neurobiological mechanisms underlying disease progression in progressive apraxia of speech. The first objective of the study is to determine the regional distribution and progressive spread of tau uptake using tau PET imaging. The second objective is then to using resting-state and task-based functional MRI and diffusion tensor tractography to characterize how disruptions in functional and structural connectivity within and across brain networks progress over time, and how these changes are related to regional tau uptake. Our last objective is then to investigate correlations between these neuroimaging measures and clinical disease progression. To accomplish these aims we will recruit 50 patients with progressive apraxia of speech, and each patient will undergo two serial assessments one year apart. At each assessment, patients will have a neurological and speech-language assessment, tau-PET scan using the [18F]AV-1451 ligand and a 3T magnetic resonance imaging scan that will include resting-state functional MRI and diffusion tensor imaging sequences. A subset of patients will also undergo a short task-based fMRI scan to allow us to assess brain activity related to speech articulation. Our analysis will assess abnormalities in these modalities within the motor speech network of regions, particularly premotor and motor cortex, and determine how dysfunction within this network changes over time and whether the disease spreads to involve other networks. We will calculate tau-PET uptake in a standard set of regions-of-interest and then measure both structural and functional connectivity between these regions-of-interest. This approach will allow us to assess multi-modal correlations and determine how these different disease mechanisms are related to each other as well as clinical decline. This mechanistic approach will increase our understanding of disease progression and the relationship between pathological processes and brain connectivity in progressive apraxia of speech; knowledge that may help improve diagnostic specificity and will be critical for the future development of mechanistically based therapies.